The research proposed in this application focuses on the study of structure-activity relationship of the thyrotropin releasing hormone receptor (TRHR) and the dynamics of agonist binding. The major practical goal of this proposal is to explore mechanisms by which the extracellular domain of TRHR affects the receptor selectivity in its specificity of interaction with agonists and in its efficacy. The proposed work will use well established methods of computer simulation and theoretical chemistry. Improved knowledge of these mechanisms will in the long run contribute to the design of agonists with enhanced specificity and whose effects will improve the receptors efficacy.